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831.
Linda Odenthal-Hesse Ingrid L. Berg Amelia Veselis Alec J. Jeffreys Celia A. May 《PLoS genetics》2014,10(2)
Meiotic recombination ensures the correct segregation of homologous chromosomes during gamete formation and contributes to DNA diversity through both large-scale reciprocal crossovers and very localised gene conversion events, also known as noncrossovers. Considerable progress has been made in understanding factors such as PRDM9 and SNP variants that influence the initiation of recombination at human hotspots but very little is known about factors acting downstream. To address this, we simultaneously analysed both types of recombinant molecule in sperm DNA at six highly active hotspots, and looked for disparity in the transmission of allelic variants indicative of any cis-acting influences. At two of the hotspots we identified a novel form of biased transmission that was exclusive to the noncrossover class of recombinant, and which presumably arises through differences between crossovers and noncrossovers in heteroduplex formation and biased mismatch repair. This form of biased gene conversion is not predicted to influence hotspot activity as previously noted for SNPs that affect recombination initiation, but does constitute a powerful and previously undetected source of recombination-driven meiotic drive that by extrapolation may affect thousands of recombination hotspots throughout the human genome. Intriguingly, at both of the hotspots described here, this drive favours strong (G/C) over weak (A/T) base pairs as might be predicted from the well-established correlations between high GC content and recombination activity in mammalian genomes. 相似文献
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Patterns of growth and tract formation during the early development of secondary lineages in the Drosophila larval brain 下载免费PDF全文
Jennifer K. Lovick Angel Kong Jaison J. Omoto Kathy T. Ngo Amelia Younossi‐Hartenstein Volker Hartenstein 《Developmental neurobiology》2016,76(4):434-451
The Drosophila brain consists of a relatively small number of invariant, genetically determined lineages which provide a model to study the relationship between gene function and neuronal architecture. In following this long‐term goal, we reconstruct the morphology (projection pattern and connectivity) and gene expression patterns of brain lineages throughout development. In this article, we focus on the secondary phase of lineage morphogenesis, from the reactivation of neuroblast proliferation in the first larval instar to the time when proliferation ends and secondary axon tracts have fully extended in the late third larval instar. We have reconstructed the location and projection of secondary lineages at close (4 h) intervals and produced a detailed map in the form of confocal z‐projections and digital three‐dimensional models of all lineages at successive larval stages. Based on these reconstructions, we could compare the spatio‐temporal pattern of axon formation and morphogenetic movements of different lineages in normal brain development. In addition to wild type, we reconstructed lineage morphology in two mutant conditions. (1) Expressing the construct UAS‐p35 which rescues programmed cell death we could systematically determine which lineages normally lose hemilineages to apoptosis. (2) so‐Gal4‐driven expression of dominant‐negative EGFR ablated the optic lobe, which allowed us to conclude that the global centrifugal movement normally affecting the cell bodies of lateral lineages in the late larva is causally related to the expansion of the optic lobe, and that the central pattern of axonal projections of these lineages is independent of the presence or absence of the optic lobe. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 434–451, 2016 相似文献
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Amelia E Firor Alexander Jares Yupo Ma 《Experimental biology and medicine (Maywood, N.J.)》2015,240(8):1087-1098
In the past 50 years, disease burden has steadily shifted from infectious disease to cancer. Standard chemotherapy has long been the mainstay of cancer medical management, and despite vast efforts towards more targeted and personalized drug therapy, many cancers remain refractory to treatment, with high rates of relapse and poor prognosis. Recent dramatic immunotherapy clinical trials have demonstrated that engineering T-cells with chimeric antigen receptors (CARs) to target CD19 can lead to complete remission in relapsed or refractory B-cell malignancies, generating a great deal of enthusiasm in the field. Here we provide a comprehensive overview of the history of adoptive T-cell therapy, including CARs, in solid tumors as well as hematologic malignancies. CAR therapy has the potential to fundamentally transform cancer treatment with specific and even personalized targeting of tissue- and tumor-specific antigens. However, before CARs become standard first-line treatment modalities, critical issues regarding efficacy, combinatorial regimens, and mechanisms of treatment failure and toxicity will need to be addressed. 相似文献
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Amelia B. Karlsson Jacqueline Washington Valentina Dimitrova Christopher Hooper Alexander Shekhtman Joanna C. Bakowska 《Molecular biology of the cell》2014,25(8):1355-1365
Troyer syndrome is an autosomal recessive hereditary spastic paraplegia (HSP) caused by frameshift mutations in the SPG20 gene that results in a lack of expression of the truncated protein. Spartin is a multifunctional protein, yet only two conserved domains—a microtubule-interacting and trafficking domain and a plant-related senescence domain involved in cytokinesis and mitochondrial physiology, respectively—have been defined. We have shown that overexpressed spartin binds to the Ile44 hydrophobic pocket of ubiquitin, suggesting spartin might contain a ubiquitin-binding domain. In the present study, we demonstrate that spartin contributes to the formation of dendritic aggresome-like induced structures (DALIS) through a unique ubiquitin-binding region (UBR). Using short hairpin RNA, we knocked down spartin in RAW264.7 cells and found that DALIS frequency decreased; conversely, overexpression of spartin increased the percentage of cells containing DALIS. Using nuclear magnetic resonance spectroscopy, we characterized spartin''s UBR and defined the UBR''s amino acids that are key for ubiquitin binding. We also found that spartin, via the UBR, binds Lys-63–linked ubiquitin chains but does not bind Lys-48–linked ubiquitin chains. Finally, we demonstrate that spartin''s role in DALIS formation depends on key residues within its UBR. 相似文献
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Nuclear pores in the apoptotic cell 总被引:2,自引:0,他引:2
Elisabetta Falcieri Pietro Gobbi Amelia Cataldi Loris Zamai Irene Faenza Marco Vitale 《The Histochemical journal》1994,26(9):754-763
Summary During apoptosis, nuclear pores undergo strong modifications, which are described here in five different apoptotic models. Conventional electron microscopy, supported by freeze-fracture analysis, showed a constant migration of nuclear pores towards the diffuse chromatin areas. In contrast, dense chromatin areas appear pore-free and are frequently surrounded by strongly dilated cisternae. A possible functional significance of this pore behaviour during apoptosis is discussed. 相似文献